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Background and Purpose: Data on long-term survival after intracerebral hemorrhage (ICH) are scarce. In a population-based nested case-control study, we compared long-term survival and causes of death within 5 years in 30-day survivors of first-ever ICH and controls, assessed the impact of cardiovascular risk factors on 5-year mortality, and analyzed time trend in 5-year mortality in ICH patients over 2 decades. Methods: We included 219 participants from the population-based Tromsø Study, who after the baseline participation had a first-ever ICH between 1994 to 2013 and 1095 age- and sex-matched participants without ICH. Cumulative survival was presented using the Kaplan-Meier method. Hazard ratios (HRs) for mortality and for the association between cardiovascular risk factors and 5-year mortality in 30-day survivors were estimated by stratified Cox proportional hazards models. Trend in 5-year mortality was assessed by logistic regression. Results: Risk of death during follow-up (median time, 4.8 years) was increased in the ICH group compared with controls (HR, 1.62 [95% CI, 1.27–2.06]). Cardiovascular disease was the leading cause of death, with a higher proportion in ICH patients (22.9% versus 9.0%; P Conclusions: Survival rates were significantly lower in cases than in controls, driven by a 2-fold increased risk of cardiovascular death. Smoking, serum cholesterol, and use of anticoagulant drugs were associated with increased risk of death in ICH patients. Five-year mortality rates in ICH patients remained stable over time.

Current evidence supports the use of intravenous thrombolysis with alteplase in patients with wake-up stroke selected with MRI or perfusion imaging and is recommended in clinical guidelines. However, access to advanced imaging techniques is often scarce. We aimed to determine whether thrombolytic treatment with intravenous tenecteplase given within 4·5 h of awakening improves functional outcome in patients with ischaemic wake-up stroke selected using non-contrast CT.TWIST was an investigator-initiated, multicentre, open-label, randomised controlled trial with blinded endpoint assessment, conducted at 77 hospitals in ten countries. We included patients aged 18 years or older with acute ischaemic stroke symptoms upon awakening, limb weakness, a National Institutes of Health Stroke Scale (NIHSS) score of 3 or higher or aphasia, a non-contrast CT examination of the head, and the ability to receive tenecteplase within 4·5 h of awakening. Patients were randomly assigned (1:1) to either a single intravenous bolus of tenecteplase 0·25 mg per kg of bodyweight (maximum 25 mg) or control (no thrombolysis) using a central, web-based, computer-generated randomisation schedule. Trained research personnel, who conducted telephone interviews at 90 days (follow-up), were masked to treatment allocation. Clinical assessments were performed on day 1 (at baseline) and day 7 of hospital admission (or at discharge, whichever occurred first). The primary outcome was functional outcome assessed by the modified Rankin Scale (mRS) at 90 days and analysed using ordinal logistic regression in the intention-to-treat population. This trial is registered with EudraCT (2014-000096-80), ClinicalTrials.gov (NCT03181360), and ISRCTN (10601890).From June 12, 2017, to Sept 30, 2021, 578 of the required 600 patients were enrolled (288 randomly assigned to the tenecteplase group and 290 to the control group [intention-to-treat population]). The median age of participants was 73·7 years (IQR 65·9-81·1). 332 (57%) of 578 participants were male and 246 (43%) were female. Treatment with tenecteplase was not associated with better functional outcome, according to mRS score at 90 days (adjusted OR 1·18, 95% CI 0·88-1·58; p=0·27). Mortality at 90 days did not significantly differ between treatment groups (28 [10%] patients in the tenecteplase group and 23 [8%] in the control group; adjusted HR 1·29, 95% CI 0·74-2·26; p=0·37). Symptomatic intracranial haemorrhage occurred in six (2%) patients in the tenecteplase group versus three (1%) in the control group (adjusted OR 2·17, 95% CI 0·53-8·87; p=0·28), whereas any intracranial haemorrhage occurred in 33 (11%) versus 30 (10%) patients (adjusted OR 1·14, 0·67-1·94; p=0·64).In patients with wake-up stroke selected with non-contrast CT, treatment with tenecteplase was not associated with better functional outcome at 90 days. The number of symptomatic haemorrhages and any intracranial haemorrhages in both treatment groups was similar to findings from previous trials of wake-up stroke patients selected using advanced imaging. Current evidence does not support treatment with tenecteplase in patients selected with non-contrast CT.Norwegian Clinical Research Therapy in the Specialist Health Services Programme, the Swiss Heart Foundation, the British Heart Foundation, and the Norwegian National Association for Public Health.

Background Stroke remains the second leading cause of deaths and disability globally, with highest mortality in Africa (low- and middle-income countries). It is crucial for healthcare professionals to have sufficient stroke risk factors' knowledge in order to reduce the stroke burden. Aims We investigated healthcare professionals' knowledge of modifiable stroke risk factors, and identified demographic factors influencing this knowledge. Methods In this cross-sectional survey study from Botswana (upper middle-income country), structured questionnaires reflecting recent stroke guidelines were administered to a representative selection of healthcare workers in greater Gaborone. The response rate was 61.4%, comprising 84 doctors, 227 nurses and 33 paramedics. Categorical data were described using percentages and Chi-square tests. Associations between stroke risk factors' knowledge and demographic factors were analyzed with one-way ANOVA using SPSS 25 statistical software. Results Awareness rate of individual stroke risk factors was highest for hypertension (96.5%), followed by obesity (93.3%), smoking (91.9%), elevated total cholesterol (91.0%), physical inactivity (83.4%), elevated low-density lipoprotein (LDL) cholesterol (81.1%), excessive alcohol drinking (77.0%), and lowest for diabetes (73.3%). For all-8 risk factors, doctors had the highest knowledge, followed by nurses and paramedics lowest (7.11 vs 6.85 vs 6.06, P, Highlights • This is the first study in Africa assessing knowledge of stroke risk factors among the three healthcare professions concurrently • Understanding stroke risk factors is crucial for healthcare professionals as counsellors and managers of stroke • Doctors had highest stroke knowledge, followed by nurses and lowest paramedics. • Low knowledge was associated with paramedics, private sector, 0–1 year’ clinical experience and female gender. • Continuing education on ischemic stroke risk factors is needed

Background: Studies on the association between long‐chained n‐3 polyunsaturated fatty acids (n‐3 PUFAs) and risk of venous thromboembolism (VTE) are conflicting, potentially due to challenges related to assessment of n‐3 PUFA intake and changes in diet during follow‐up. Objectives: To investigate whether dietary intake of marine n‐3 PUFAs was associated with risk of incident VTE in a population‐based cohort with repeated assessments of n‐3 PUFA intake. Methods: We recruited 21 970 participants (after excluding 7570 with incomplete data) from the fourth (1994‐1995) and sixth (2007‐2008) surveys of the Tromsø Study, and recorded incident VTEs up to 2016. Intake of n‐3 PUFAs was computed from self‐reported consumption of fat and lean fish, fish spread, and supplements. Cox proportional hazards regression models with n‐3 PUFA intake as a time‐varying variable were used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) for VTE across quartiles (Q) of n‐3 PUFA intake. Results: There were 541 incident VTEs during follow‐up. Compared to Q1, subjects in Q2‐4 had 22%‐26% lower risk of VTE (HR Q2 0.74, 95% CI 0.57‐0.96; HR Q3 0.77, 95% CI 0.59‐0.99; HR Q4 0.78, 95% CI 0.61‐1.00). The association was most pronounced for provoked VTE, particularly provoked pulmonary embolism (PE), with risk estimates of 0.42 (95% CI 0.25‐0.72), 0.40 (95% CI 0.23‐0.68), and 0.61 (95% CI 0.38‐0.96) for Q2‐4, respectively. Conclusions: Dietary intake of marine n‐3 PUFAs was associated with a lower risk of VTE, particularly provoked PE. The association displayed a threshold pattern and suggested a protective effect of an n‐3 PUFA intake ≥4.7 g/week.

While APOE ɛ4 is the major genetic risk factor for Alzheimer’s disease (AD), amyloid dysmetabolism is an initial or early event predicting clinical disease and is an important focus for secondary intervention trials. To improve identification of cases with increased AD risk, we evaluated recruitment procedures using pathological CSF concentrations of Aβ42 (pAβ) and APOE ɛ4 as risk markers in a multi-center study in Norway. In total, 490 subjects aged 40–80 y were included after response to advertisements and media coverage or memory clinics referrals. Controls (n = 164) were classified as normal controls without first-degree relatives with dementia (NC), normal controls with first-degree relatives with dementia (NCFD), or controls scoring below norms on cognitive screening. Patients (n = 301) were classified as subjective cognitive decline or mild cognitive impairment. Subjects underwent a clinical and cognitive examination and MRI according to standardized protocols. Core biomarkers in CSF from 411 and APOE genotype from 445 subjects were obtained. Cases (both self-referrals (n = 180) and memory clinics referrals (n = 87)) had increased fractions of pAβ and APOE ɛ4 frequency compared to NC. Also, NCFD had higher APOE ɛ4 frequencies without increased fraction of pAβ compared to NC, and cases recruited from memory clinics had higher fractions of pAβ and APOE ɛ4 frequency than self-referred. This study shows that memory clinic referrals are pAβ enriched, whereas self-referred and NCFD cases more frequently are pAβ negative but at risk (APOE ɛ4 positive), suitable for primary intervention.

Venous thromboembolism (VTE) is associated with increased risk of arterial cardiovascular diseases (CVD), and development of atherosclerosis secondary to VTE may be an intermediate between VTE and CVD. Therefore, we aimed to investigate whether incident VTE was associated with subsequent carotid atherosclerosis formation and progression in a population-based observational study. Subjects attending two or more ultrasound examinations of the right carotid artery, with measurement of total plaque area (TPA), in the Tromsø Study in 1994–1995, 2001–2002, and/or 2007–2008 were eligible. We identified 150 subjects diagnosed with first-lifetime VTE between the initial and follow-up visit, and randomly selected 600 age- and sex-matched subjects without VTE between the visits. Subjects with VTE and carotid plaque(s) at the first visit had 4.1 mm2 (β: 4.13, 95% CI: −1.72 to 9.98) larger change in TPA between the first and second visit compared with subjects without VTE after adjustment for change in high-sensitivity C-reactive protein (hs-CRP) and traditional atherosclerotic risk factors. The association remained after restricting the analyses to VTE events diagnosed in the first half of the time interval between the carotid ultrasounds (β: 4.02, 95% CI: −3.66 to 11.70), supporting that the change in TPA occurred subsequent to the VTE. No association was found between VTE and novel carotid plaque formation. In conclusion, we found a possible association between VTE and atherosclerosis progression in those with already established carotid plaques, but not between VTE and novel plaque formation. The association between VTE and carotid plaque progression was not mediated by low-grade inflammation assessed by hs-CRP.

Background and Purpose— It is proposed that 20% to 40% of the decline in first-ever stroke incidence is attributed to the improvement of risk factor control. We estimated the impact of modifiable cardiovascular risk factors on the changing incidence of ischemic stroke (IS) between 1995 and 2012, using individual person data from repeated surveys in a general population. Methods— The proportion of the IS incidence decline explained by change in each risk factor over time was estimated from 1995 to 2012 by Poisson regression among 26 329 participants who attended the fourth Tromsø survey in 1994 to 1995. Hazard ratios for IS were estimated with Cox proportional hazards regression among 27 936 participants who attended at least 1 of the Tromsø surveys in 1994 to 1995, 2001, or 2007 to 2008. Age- and sex-adjusted means or prevalences of risk factors over time were estimated by generalized estimating equations. Results— There were 1226 first-ever IS during 367 636 person-years of follow-up. Changes in cardiovascular risk factors accounted for 57% of the decrease in IS incidence from 1995 to 2012. The most important contributors were decreasing mean systolic blood pressure and smoking prevalence, accounting for 26% and 17% of the observed decline, respectively. Conversely, increasing diabetes mellitus prevalence contributed negatively to the declining IS incidence. Conclusions— Changes in cardiovascular risk factors explained 57% of the decrease in IS incidence from 1995 to 2012. Reduction in systolic blood pressure and prevalence of smoking were the most important contributors.

Background: Subjective cognitive decline (SCD) is associated with an increased risk of Alzheimer’s disease (AD). However, patients reporting SCD to their general practitioner are not always referred to a memory clinic. Objective: To investigate whether prior history of medical help-seeking is associated with AD biomarker abnormality, worse cognitive performance, and/or depressive symptoms in SCD. Methods: We compared levels of cerebrospinal fluid (CSF) Aβ1 - 42, cognitive performance, and depressive symptoms (15-item Geriatric Depression Scale, GDS-15) between healthy controls (n = 88), SCD with a history of medical help seeking (SCD-HS, n = 67), and SCD non help-seekers (SCD-NHS, n = 44). Cases with evidence of amyloid plaques (CSF Aβ1 - 42 ≤708 ng/l) and symptoms of depression (GDS-15≥6) were determined in both SCD groups. Results: The SCD-HS group had lower CSF Aβ1 - 42 (p p n = 12, 18%) and amyloid plaques (n = 18, 27%) compared to SCD-NHS (n = 1, 2% and n = 7, 16%, respectively). None of the SCD-HS cases and only one SCD-NHS case had concurrent symptoms of depression and amyloid plaques. The SCD-HS cases showed equal word list learning and memory performance regardless of amyloid status or symptoms of depression. Conclusion: Medical help-seeking in SCD is associated with an increased risk of AD pathology or symptoms of depression. However, subtle memory deficits are seen in SCD help-seekers, also without amyloid plaques or symptoms of depression.

Background/Objective: In recent years, several slightly younger cohorts have been established in order to study the preclinical and prodromal phases of dementia. The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) wordlist memory test (WLT) is widely used in dementia research. However, culturally adapted and demographically adjusted test norms for younger ages are lacking. Method: This paper investigates effects of age, gender and years of education on test performance and offers demographically adjusted norms for the CERAD WLT using a regression-based norming procedure for the age span 40–80years based on healthy controls (n¼227) from the Norwegian “Dementia Disease Initiation” (DDI) (n¼168) and “Trønderbrain” (n¼59) cohorts. In order to evaluate normative performance, we apply the norms to an independent sample of persons diagnosed with mild cognitive impairment (MCI = 168) and perform multiple regression analyses to evaluate adjustment of pertinent demographics. Results: CERAD WLT norms adjusted for effects of age, gender and educational level are proposed. The norms successfully adjusted for effects of age, gender and education in an independent sample of Norwegians with MCI. Conclusion: Demographically adjusted norms for the CERAD WLT for ages 40–80years based on a Norwegian sample are proposed. To our knowledge, this is the first normative study of this test to offer demographically adjusted norms for this age span. 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.

AimsAveraged measurements, but not the progression based on multiple assessments of carotid intima-media thickness, (cIMT) are predictive of cardiovascular disease (CVD) events in individuals. Whether this is true for conventional risk factors is unclear.Methods and resultsAn individual participant meta-analysis was used to associate the annualised progression of systolic blood pressure, total cholesterol, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol with future cardiovascular disease risk in 13 prospective cohort studies of the PROG-IMT collaboration ( n = 34,072). Follow-up data included information on a combined cardiovascular disease endpoint of myocardial infarction, stroke, or vascular death. In secondary analyses, annualised progression was replaced with average. Log hazard ratios per standard deviation difference were pooled across studies by a random effects meta-analysis. In primary analysis, the annualised progression of total cholesterol was marginally related to a higher cardiovascular disease risk (hazard ratio (HR) 1.04, 95% confidence interval (CI) 1.00 to 1.07). The annualised progression of systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol was not associated with future cardiovascular disease risk. In secondary analysis, average systolic blood pressure (HR 1.20 95% CI 1.11 to 1.29) and low-density lipoprotein cholesterol (HR 1.09, 95% CI 1.02 to 1.16) were related to a greater, while high-density lipoprotein cholesterol (HR 0.92, 95% CI 0.88 to 0.97) was related to a lower risk of future cardiovascular disease events.ConclusionAveraged measurements of systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol displayed significant linear relationships with the risk of future cardiovascular disease events. However, there was no clear association between the annualised progression of these conventional risk factors in individuals with the risk of future clinical endpoints.

Background Studies on the relationship between temporal trends in risk factors and incidence rates of intracerebral hemorrhage are scarce. Aims To analyze temporal trends in risk factors and incidence rates of intracerebral hemorrhage using individual data from a population-based study. Methods We included 28,167 participants of the Tromsø Study enrolled between 1994 and 2008. First-ever intracerebral hemorrhages were registered through 31 December 2013. Hazard ratios (HRs) for intracerebral hemorrhage were analyzed by Cox proportional hazards models, risk factor levels over time by generalized estimating equations, and incidence rate ratios (IRR) by Poisson regression. Results We registered 219 intracerebral hemorrhages. Age, male sex, systolic blood pressure (BP), diastolic BP, and hypertension were associated with intracerebral hemorrhage. Hypertension was more strongly associated with non-lobar intracerebral hemorrhage (HR 5.08, 95% CI 2.86–9.01) than lobar intracerebral hemorrhage (HR 1.91, 95% CI 1.12–3.25). In women, incidence decreased significantly (IRR 0.46, 95% CI 0.23–0.90), driven by a decrease in non-lobar intracerebral hemorrhage. Incidence rates in men remained stable (IRR 1.27, 95% CI 0.69–2.31). BP levels were lower and decreased more steeply in women than in men. The majority with hypertension were untreated, and a high proportion of those treated did not reach treatment goals. Conclusions We observed a significant decrease in intracerebral hemorrhage incidence in women, but not in men. A steeper BP decrease in women may have contributed to the diverging trends. The high proportion of untreated and sub-optimally treated hypertension calls for improved strategies for prevention of intracerebral hemorrhage.

Source at: http://doi.org/10.1186/s12937-018-0364-8 Background: Whether long-chain n–3 PUFAs of marine origin have an anti-atherogenic effect in the general population has hardly been studied. In this population-based study, we hypothesized that fatty fish and fish oil intake protect against development of novel atherosclerotic plaques and is associated with reduced plaque size. Methods: We obtained questionnaire-based information on fish consumption and carotid ultrasonography from 3900 persons aged 45–74 years. The questionnaires were validated by measuring serum concentrations of PUFAs and triglycerides in a subgroup. At follow-up seven years later, 2983 (76%) went through a second ultrasound scanning. Logistic regression and general linear models were used to analyze the outcome (plaque presence and plaque area) as a function of fish consumption, including analyses stratified on fish oil supplements. Results: At baseline, lean fish intake < 1 time/week vs. 1–1.9 times/week was associated with risk of plaque (OR 1.34, 95% CI 1.03–1.76). Fatty fish intake and use of fish oil supplements were not statistically significantly associated with atherosclerosis at baseline. In persons without plaque at baseline, total fish consumption ≥3 times/week vs. 1–1.9 times/week was associated with risk of novel plaque (OR 1.32, 95% CI 1.01–1.73) and larger plaque area (1.76 mm2 vs. 1.46 mm2 , p = 0.02) at follow-up. Adjustments for use of fish oil supplements had no impact on the associations, and no interactions were seen between total, fatty or lean fish consumption and fish oil intake. Conclusions: We found no protective effect of fatty fish eating or fish oil supplements on atherosclerotic plaque formation or plaque area in a general population. Lean fish consumption was associated with a reduced risk for plaque in cross-sectional analysis, suggesting that the beneficial effects of fish consumption on atherosclerosis may be mediated through other mechanisms than n-3 PUFAs.

Background The joint effect of atherosclerosis and CRP (C‐reactive protein) on risk of ischemic stroke ( IS ) and myocardial infarction ( MI ) has been sparsely studied. The aim of this study was to explore whether CRP mediates the risk of events in subjects with prevalent carotid plaque, examine synergism, and test whether CRP and carotid plaque add to risk prediction beyond traditional risk factors. Methods and Results CRP and carotid total plaque area ( TPA ) were measured in 10 109 participants in the Tromsø Study from 1994 to 2008. Incident IS (n=671) and MI (n=1079) were registered until December 31, 2013. We calculated hazard ratios (HRs) of MI and IS according to categories of CRP (3 mg/L) and plaque status (no plaque and TPA below and above median) in Cox proportional hazard models with time‐varying covariates. Multivariable‐adjusted CRP >3 versus IS ( HR , 1.84; 95% confidence interval, 1.49–2.26) and MI ( HR, 1.46; 95% confidence interval, 1.23–1.73). TPA above median versus no plaque was associated with risk for IS ( HR , 1.65; 95% confidence interval, 1.36–2.01) and MI ( HR , 1.64; 95% confidence interval, 1.41–1.92). In participants with plaque, adjustment for CRP minimally attenuated the risk estimates. The highest incidence rates for MI and IS were seen in the group with both CRP >3 mg/L and TPA is above the median. TPA and CRP combined added to risk prediction beyond traditional risk factors. Conclusions The simultaneous presence of subclinical atherosclerosis and elevated CRP was associated with increased risk of IS and MI . The combined assessment of subclinical atherosclerosis and inflammatory biomarkers may improve cardiovascular disease risk stratification.

Background The clinical use of carotid intima media thickness (cIMT) requires normal values, which may be subject to variation of geographical factors, ethnicity or measurement details. The influence of these factors has rarely been studied. The aim of this study was to determine whether normative cIMT values and their association with event risk are generalizable across populations. Design Meta-analysis of individual participant data. Method From 22 general population cohorts from Europe, North America and Asia we selected subjects free of cardiovascular disease. Percentiles of cIMT and cIMT progression were assessed separately for every cohort. Cox proportional hazards models for vascular events were used to estimate hazard ratios for cIMT in each cohort. The estimates were pooled across Europe, North America and Asia, with random effects meta-analysis. The influence of geography, ethnicity and ultrasound protocols on cIMT values and on the hazard ratios was examined by meta-regression. Results Geographical factors, ethnicity and the ultrasound protocol had influence neither on the percentiles of cIMT and its progression, nor on the hazard ratios of cIMT for vascular events. Heterogeneity for percentiles of cIMT and cIMT progression was too large to create meaningful normative values. Conclusions The distribution of cIMT values is too heterogeneous to define universal or regional population reference values. CIMT values vary widely between different studies regardless of ethnicity, geographic location and ultrasound protocol. Prediction of vascular events with cIMT values was more consistent across all cohorts, ethnicities and regions.

Background and Purpose: In patients with acute stroke, undernutrition and aspiration pneumonia are associated with increased mortality and length of hospital stay. Formal screening for nutritional risk and dysphagia helps to ensure optimal nutritional management in all patients with stroke and to reduce the risk of aspiration in patients with dysphagia. We developed a national guideline for nutritional and dysphagia screening in acute stroke, which was introduced in our stroke unit on June 1, 2012. The primary objective was to audit adherence to the guideline and to achieve full implementation. Second, we assessed the prevalence of nutritional risk and dysphagia. Methods: We performed a chart review to assess performance of screening for nutritional risk and dysphagia in all patients with stroke hospitalized for ≥48 hours between June 1, 2012, and May 31, 2013. Next we applied a “clinical microsystems approach” with rapid improvement cycles and audits over a 6-month period to achieve full implementation. Results: The chart review showed that nutritional risk screening was performed in 65% and swallow testing in 91% of eligible patients (n = 185). Proactive implementation resulted in >95% patients screened (n = 79). The overall prevalence of nutritional risk was 29%, and 23% of the patients failed the initial swallow test. Conclusions: Proactive implementation is required to obtain high screening rates for nutritional risk and swallowing difficulties using validated screening tools. The proportion of patients at nutritional risk and the prevalence of dysphagia at initial swallow test were in the lower range of previous reports.

Background and aims Novel biomarkers are linked to cardiovascular disease (CVD). The aim of the present study was to investigate the association between 28 blood biomarkers and the formation and progression of carotid plaque. Methods In a nested case control study with 703 participants from the population based Tromso Study, a large biomarker panel was measured in blood obtained at baseline. Carotid ultrasound was assessed both at baseline and at 6 years of follow-up. Four groups were defined: Group 1: no plaque at baseline or at follow-up (reference group); Group 2: novel plaque at follow-up; Group 3: stable plaque at follow-up; Group 4: progression of plaque at follow-up. By multinomial logistic regression analyses, we assessed the risk of being in the different plaque groups with regard to traditional cardiovascular risk factors and levels of biomarkers at baseline. Results Adjusted for traditional risk factors, interleukin-6 (IL-6) was an independent predictor of plaque progression (OR 1.44, 95% CI 1.12–1.85 per SD increase in IL-6 level). This result remained significant after inclusion of other novel biomarkers to the model, and when subjects with former CVD were excluded. Neopterin was protective of novel plaque formation (OR 0.73, 95% CI 0.57–0.93). Myeloperoxidase and Caspase-1 were independent predictors of plaque progression, but this effect disappeared when excluding subjects with former CVD. Conclusions IL-6 is an independent predictor of plaque progression, suggesting that it may be a marker of progressive atherosclerosis in the general population and that its central role in CVD may be related to promotion of plaque growth.

The following article, Bekkelund, S.I. & Johnsen, S.H. (2018). Creatine kinase is associated with reduced inflammation in a general population: The Tromsø study. PLoS ONE, 13(5), can be accessed at https://doi.org/10.1371/journal.pone.0198133. Background: Creatine kinase (CK) has been associated with reduced inflammation in obesity while inflammation is associated with obesity-related cardiovascular diseases. We investigated the relationship between CK and high sensitive C-reactive protein (hs-CRP) in a general population. Methods: CK and hs-CRP were measured in the population-based Tromsø study that included entire birth cohorts and random samples of citizens between 30–87 years of age. The analyses were performed sex-stratified in 5969 men and 6827 women. Results: CK correlated negatively with hs-CRP in men (r = -0.08, P Conclusion: CK were inversely and independently associated with hs-CRP in a general population. These data provide evidence that CK might have anti-inflammatory properties, but the mechanism and clinical implications are unclarified.

This is the peer reviewed version of the following article: Småbrekke, B., Rinde, L.B.R., Mathisen Hald, E.M., Njølstad, I., Mathiesen, E.B., Johnsen, S.H., ... Lijfering, W.M. (2017). Repeated measurements of carotid atherosclerosis and future risk of venous thromboembolism: the Tromsø Study. Journal of Thrombosis and Haemostasis, 16(12), 2344-2351, which has been published in final form at https://doi.org/10.1111/jth.13858. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. Background: Whether a relationship between atherosclerosis and subsequent venous thromboembolism (VTE) exists is controversial. Objective: To investigate the association between carotid atherosclerosis and VTE by using repeated measurements of intima media thickness (IMT) and total plaque area (TPA) in participants recruited from the general population. Methods: Participants were recruited from the fourth (1994–1995), fifth (2001–2002) and sixth (2007–2008) surveys of the Tromsø Study. In total, 10 426 participants attended, for whom measurements of carotid IMT and TPA and potential confounders were updated at each available survey. Time‐varying Cox regression models were used to calculate hazard ratios (HRs) of VTE across various levels of IMT and TPA adjusted for age, sex, and body mass index. Results: There were 368 incident VTE events during a median follow‐up of 10.8 years. Participants with increasing IMT were, on average, older and had a less favorable cardiovascular risk profile. There was no association between tertiles of increasing TPA and the risk of VTE in the time‐varying model, and increasing IMT was not associated with an increased risk of VTE (HR 0.96, 95% confidence interval [CI] 0.86–1.07). Neither plaque formation nor plaque progression was associated with the risk of VTE (respectively: HR 1.00, 95% CI 0.98–1.02; and HR 0.96, 95% CI 0.84–1.11). Conclusion: Carotid IMT and TPA were not associated with an increased risk of VTE in time‐varying analyses. Furthermore, there was no association between plaque initiation or plaque progression and subsequent VTE.

BACKGROUND AND AIMS: Few studies have investigated the association of different measures of adiposity with carotid plaque. We aimed to investigate and compare the associations of four measures of adiposity: body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR) with the presence of carotid plaque and total plaque area (TPA) in the right carotid artery. METHODS: We included 4906 individuals aged 31-88 years who participated in a population-based study with ultrasonography of the right carotid artery. Adiposity measures were converted to sex-specific SD units to allow comparison of effect sizes. TPA was log transformed due to its skewed distribution. Logistic and linear regression models were used respectively to investigate the association of each adiposity measure with the presence of plaque and with log-transformed TPA. Estimates were adjusted for potential confounders and mediators such as blood pressure and lipids. RESULTS: After adjustment for age, sex, smoking, and education level, there was strong evidence of an association between all adiposity measures and log-transformed TPA, whereas only WHR was weakly associated with presence of plaque. WHR showed the largest adjusted effect size for both log-transformed TPA (beta 0.055, 95%CI 0.028-0.081) and the presence of plaque (OR 1.07, 95%CI 1.01-1.15). Adjustment for mediators led to appreciable attenuation of observed effects. CONCLUSIONS: Adiposity is more consistently associated with extent of plaque burden than with whether an individual does or does not have any plaque. There was evidence that established biomarkers mediate much of this association. Abdominal adiposity appears to show the strongest effect.

CRP predicts cardiovascular disease (CVD) in large epidemiologic studies. The aim of the present study was to elucidate the role of CRP in atherosclerosis formation and progression in a prospective population-based study.6503 middle-aged subjects from The Tromsø study had serum CRP, carotid ultrasound and complete covariate data collected at baseline in 1994. Of these, 4730 and 2917 attended follow-up surveys with repeated assessments in 2001 and 2007, respectively. The cross-sectional associations between CRP and subclinical carotid atherosclerosis, and the longitudinal associations between baseline CRP and novel plaque formation and plaque progression were assessed in generalized estimating equations and linear mixed models stratified by sex.At baseline, traditional risk factors and plaque prevalence increased by CRP risk categories (1 mg/L, 1-3 mg/L, and3 mg/L) in both sexes. In cross-sectional analyses, multivariable-adjusted CRP was associated with plaque prevalence and total plaque area (TPA) in men and women. Age-adjusted baseline CRP3 mg/L compared to CRP1 mg/L predicted novel plaque formation (OR 1.44, CI 1.08-1.92) and TPA progression (β = 0.0.029 (CI, 0.003-0.056)) in men, but not in women. In neither men nor women was baseline CRP a predictor of TPA-progression or novel plaque formation when adjusted for traditional risk factors.CRP was associated with plaque presence and TPA in cross-sectional analyses, but was not an independent predictor of novel plaque formation or plaque progression. Our findings suggest that CRP may link to CVD by other mechanisms than promoting formation and progression of atherosclerotic plaques.

The correlation between creatine kinase (CK) and blood pressure (BP) was examined prospectively in 120 patients with persistent high CK and 130 individuals with normal CK. Hypertension was defined as systolic BP (SBP) ≥ 140 mm Hg or diastolic BP (DBP) ≥ 90 mm Hg or current use of antihypertensive medication. Baseline CK was weakly correlated with SBP (r = 0.11, P = .07) and DBP (r = 0.16, P = .01) at follow-up. Persons with persistent high CK had higher SBP (140.8 mm Hg vs 138.2 mm Hg) and DBP (83.2 mm Hg vs 81.0 mm Hg, P = .06) values and were more likely to have hypertension (66.7% vs 55.5%, P = .05) than individuals with normal CK. In age- and sex-adjusted analysis, a 1-unit change in logCK was associated with a 4.9-mm Hg higher SBP, a 3.3-mm Hg higher DBP, and a 2.2-higher odds for having hypertension at follow-up (P = .1, .07, and .06, respectively). When including body mass index (BMI) to the model, BMI was a strong and independent predictor for SBP, DBP, and hypertension at follow-up and the CK effect on blood pressure was substantially attenuated. This study showed that the CK effect on blood pressure is clearly modified by BMI.

Background: Cognitive assessment is essential in tracking disease progression in AD. Presently, cohorts including preclinical at-risk participants are recruited by different means, which may bias cognitive and clinical features. We compared recruitment strategies to levels of cognitive functioning. Objective: We investigate recruitment source biases in self-referred and memory clinic-referred patient cohorts to reveal potential differences in cognitive performance and demographics among at-risk participants. Methods: We included 431 participants 40–80 years old. Participants were classified as controls (n = 132) or symptom group (n = 299). The symptom group comprised of subjective cognitive decline (SCD, n = 163) and mild cognitive impairment (MCI, n = 136). We compared cognitive performance and demographics in memory clinic-referrals (n = 86) to self-referred participants responding to advertisements and news bulletins (n = 179). Participants recruited by other means were excluded from analysis (n = 34). Results: At symptom group level, we found significant reductions in cognitive performance in memory clinic-referrals compared to self-referrals. However, here reductions were only found within the MCI group. We found no differences in cognitive performance due to recruitment within the SCD group. The MCI group was significantly impaired compared to controls on all measures. Significant reductions in learning, and executive functions were also found for the SCD group. Conclusion: Regardless of recruitment method, both the SCD and MCI groups showed reductions in cognitive performance compared to controls. We found differences in cognitive impairment for memory clinic-referrals compared to self-referrals only within the MCI group, SCD-cases being equally affected irrespective of referral type. © 2017 – IOS Press and the authors. All rights reserved This article is published online with Open Access and distributed under the terms of the Creative Commons Attribution Non-Commercial License (CC BY-NC 4.0).

Objectives This research aims to study how carotid atherosclerosis is related to growth of infrarenal aortic diameter and aneurysmal formation. Design Population-based follow-up study. Materials and methods At baseline, ultrasound examination of the carotid artery and the abdominal aorta was performed in 4241 persons from a general population with no evidence of abdominal aortic aneurysm (AAA). The burden of atherosclerosis was assessed as carotid total plaque area (TPA). After a mean follow-up of 6.3 years, a new ultrasound examination was performed and measurements of the aortic diameter and carotid TPA were repeated. The effects on aortic diameter progression, follow-up diameter and risk for AAA were assessed in multiple linear and logistic regression models according to carotid TPA, adjusted for known risk factors. Results When analysing AAA as a dichotomous variable, a borderline association between atherosclerosis and AAA could be demonstrated. When modelling aortic diameter as a continuous variable, a 1-SD increase in 5 years' carotid plaque area (ΔTPA) was associated with a 0.12-mm growth in infrarenal aortic diameter (standard error (SE) 0.04) and a 0.20-mm wider aorta at follow-up (SE 0.06). No independent relation was seen for baseline atherosclerosis. Conclusions Carotid plaque progression was positively related to growth in infrarenal aortic diameter and aortic diameter at follow-up. Whether this co-variation between plaque growth and aortic diameter growth is causally related or independent events is still an open question.

Background Carotid atherosclerosis is a risk factor for stroke and cognitive decline, but knowledge on how progression of carotid atherosclerosis affects cognitive function in stroke-free individuals is scarce. Methods In the population-based Tromso study, we calculated the change in ultrasound-assessed carotid plaque number and total plaque area from baseline (survey 4) to follow-up 7 years later (survey 5) in 4274 middle-aged stroke-free subjects. Cognitive function was assessed at follow-up by the verbal memory test, the digit-symbol coding test, and the tapping test and repeated after an additional 6 years in a subgroup of 2042 subjects (survey 6). Associations between the average of survey 4 and survey 5 plaque scores and the progression of plaque scores and cognitive test scores were assessed in regression analyses adjusted for baseline age, sex, education, depression, and cardiovascular risk factors. Results Progression of total plaque area was associated with lower scores in the digit-symbol coding test (multivariable adjusted standardized β, −0.03; 95% CI, −0.05 to −0.00; P = 0.04) and the tapping test (β, −0.03; 95% CI, −0.06 to −0.00; P = 0.03). Similar results were seen for progression of plaque number. The average plaque scores were associated with lower scores in all cognitive tests (P-values ≤ 0.01). No association was found between plaque scores and cognitive decline. Conclusions The average plaque scores were associated with lower scores in all cognitive tests. Progression of plaque scores was associated with lower scores in the digit-symbol coding test and the tapping test, but not with the verbal memory test or with cognitive decline.

Background: Carotid artery atherosclerosis is a major risk factor for stroke and subsequent cognitive impairment. Prospective population studies have shown associations between carotid intima-media thickness (IMT) and stenosis and cognitive decline and dementia in elderly stroke-free persons, whereas results in the middle-aged are conflicting. Methods: In this prospective population-based study, 4,371 stroke-free middle-aged participants underwent carotid ultrasound examination and assessment of vascular risk factors at baseline and were tested for cognitive function 7 years later. Associations between IMT, number of plaques and total plaque area and cognitive test scores on verbal memory test, digit symbol-coding test and tapping test were assessed in linear regression models. Results: In the multivariable analyses adjusted for sex, age, education, depression and vascular risk factors, the presence of plaques was significantly associated with lower test scores on the verbal memory test (p = 0.01) and on the digit symbol-coding test (p = 0.03). The number of plaques (p = 0.01) and the total plaque area (p = 0.02) were associated with lower scores on the verbal memory test. No significant association was seen between common carotid artery IMT and cognitive test scores. The tapping test was not associated with the carotid ultrasound variables. Conclusions: In this middle-aged general population, subclinical carotid atherosclerosis measured as the presence of plaques, number of plaques and total plaque area were independent long-term predictors of lower cognitive test scores.

Background: The presence of echolucent artery plaques is associated with increased risk of cardiovascular events as compared to echogenic plaques. Whether inflammatory markers are associated with carotid plaque morphology is questioned. Methods: 5,341 individuals were examined with ultrasonography of the right carotid artery. Of these, 3,205 had carotid plaque(s), in whom plaque area (mm2) and plaque echogenicity, expressed as the computer-assisted gray scale median (GSM), were determined. White blood cell count (WBC), fibrinogen and C-reactive protein (CRP) were analyzed, as well as other cardiovascular risk factors. In multiple linear and logistic regression models, we determined the relationship between plaque area and echogenicity, and inflammatory markers. Results: Women and men with carotid plaque(s) had significantly elevated levels of WBC and fibrinogen, but not CRP, as compared to subjects without plaques. All inflammatory markers were significantly associated with plaque area in men. WBC was significantly associated with plaque echogenicity in women, whereas no association was found between fibrinogen and CRP and plaque echogenicity in either gender. Conclusions: This cross-sectional study showed sex-dependent differences in associations between measures of carotid atherosclerosis and inflammatory markers. CRP did not discriminate echolucent from echogenic carotid plaques in either gender. Our data highlight the importance of sex-specific analyses in future studies.

In a cross-sectional, population-based study in Tromso, Norway, the authors investigated correlations between lumen diameter in the right common carotid artery (CCA) and the diameters of the femoral artery and abdominal aorta and whether CCA lumen diameter was a risk factor for abdominal aortic aneurysm (AAA). Ultrasonography was performed in 6,400 men and women aged 25-84 years during 1994-1995. An AAA was considered present if the aortic diameter at the level of renal arteries was greater than or equal to 35 mm, the infrarenal aortic diameter was greater than or equal to 5 mm larger than the diameter of the level of renal arteries, or a localized dilation of the aorta was present. CCA lumen diameter was positively correlated with abdominal aortic diameter (r = 0.3, P < 0.01) and femoral artery diameter (r = 0.2, P < 0.01). In a multivariable adjusted model, CCA lumen diameter was a significant predictor of AAA in both men and women (for the fifth quintile vs. the third, odds ratios were 1.9 (95% confidence interval: 1.2, 2.9) and 4.1 (95% confidence interval: 1.5, 10.8), respectively). Thus, CCA lumen diameter was positively correlated with femoral and abdominal aortic artery diameter and was an independent risk factor for AAA.

BACKGROUND: Large-scale epidemiological evidence on the role of inflammation in early atherosclerosis, assessed by carotid ultrasound, is lacking. We aimed to quantify cross-sectional and longitudinal associations of inflammatory markers with common-carotid-artery intima-media thickness (CCA-IMT) in the general population.METHODS: Information on high-sensitivity C-reactive protein, fibrinogen, leucocyte count and CCA-IMT was available in 20 prospective cohort studies of the PROG-IMT collaboration involving 49,097 participants free of pre-existing cardiovascular disease. Estimates of associations were calculated within each study and then combined using random-effects meta-analyses.RESULTS: Mean baseline CCA-IMT amounted to 0.74 mm (SD = 0.18) and mean CCA-IMT progression over a mean of 3.9 years to 0.011 mm/year (SD = 0.039). Cross-sectional analyses showed positive linear associations between inflammatory markers and baseline CCA-IMT. After adjustment for traditional cardiovascular risk factors, mean differences in baseline CCA-IMT per one-SD higher inflammatory marker were: 0.0082 mm for high-sensitivity C-reactive protein (p CONCLUSION: Inflammation was independently associated with CCA-IMT cross-sectionally. The lack of clear associations with CCA-IMT progression may be explained by imprecision in its assessment within a limited time period. Our findings for 'inflammatory load' suggest important combined effects of the three inflammatory markers on early atherosclerosis.

Background: The aim of this study was to explore temporal trends in incidence and case fatality rates of intracerebral hemorrhage (ICH) over the last two decades in a Norwegian municipality. Methods: Incident cases of primary ICH were registered in the period from 1995 through 2012 in 32,530 participants of the longitudinal population-based Tromsø Study. Poisson regression models were used to obtain incidence rates over time in age- and sex-adjusted and age- and sex-specific models. Case fatality rates were calculated and age- and sex-adjusted trends over time were estimated using logistic regression. Results: A total of 226 ICHs were registered. The age- and sex-adjusted incidence rate [95% confidence interval (CI)] in the overall population was 0.42 (0.37-0.48) per 1,000 person-years. Age-adjusted incidence rates were 0.53 (0.43-0.62) in men and 0.33 (0.26-0.39) in women. In individuals aged Conclusion: No significant changes in incidence and case fatality rates of ICH were observed during the last two decades.

Background and Purpose— Ultrasound of carotid arteries provides measures of intima media thickness (IMT) and plaque, both widely used as surrogate measures of cardiovascular disease. Although IMT and plaques are highly intercorrelated, the relationship between carotid plaque and IMT and cardiovascular disease has been conflicting. In this prospective, population-based study, we measured carotid IMT, total plaque area, and plaque echogenicity as predictors for first-ever myocardial infarction (MI). Methods— IMT, total plaque area, and plaque echogenicity were measured in 6226 men and women aged 25 to 84 years with no previous MI. The subjects were followed for 6 years and incident MI was registered. Results— During follow-up, MI occurred in 6.6% of men and 3.0% of women. The adjusted relative risk (RR; 95% CI) between the highest plaque area tertile versus no plaque was 1.56 (1.04 to 2.36) in men and 3.95 (2.16 to 7.19) in women. In women, there was a significant trend toward a higher MI risk with more echolucent plaque. The adjusted RR (95% CI) in the highest versus lowest IMT quartile was 1.73 (0.98 to 3.06) in men and 2.86 (1.07 to 7.65) in women. When we excluded bulb IMT from analyses, IMT did not predict MI in either sex. Conclusions— In a general population, carotid plaque area was a stronger predictor of first-ever MI than was IMT. Carotid atherosclerosis was a stronger risk factor for MI in women than in men. In women, the risk of MI increased with plaque echolucency.

Proinsulin is increased in persons at cardiovascular risk. Increased secretion of proinsulin relative to insulin has been suggested as a sign of defective conversion of proinsulin to insulin and C-peptide and is associated with beta cell dysfunction. It has also been suggested that proinsulin has more of a pro-atherogenic effect than insulin, the levels of which are also increased in the insulin resistance state. In this prospective population-based study, we examined whether the proinsulin:insulin ratio (PIR) or insulin:glucose ratio (IGR, an insulin resistance surrogate) predicted carotid plaque size in nondiabetic participants.The study included 1,859 men and 1,998 women aged 25-82 years from the Tromsø Study, who were examined with B-mode high resolution ultrasound at baseline in 1994-1995 and at follow-up in 2001-2002. All images were computer processed to yield mm(2) measures of plaque. Proinsulin and insulin were measured at baseline. All analyses were stratified for sex.After adjusting for age, baseline plaque area, BMI, cholesterol, HDL-cholesterol, HbA(1c), IGR, albumin:creatinine ratio, fibrinogen, BP and lifestyle factors (tobacco smoking, alcohol consumption, physical activity), PIR was significantly associated with plaque size at follow-up in women but not men. For each SD in the PIR in women, the mean plaque area increased by 0.97 mm(2) (95% CI 0.44-1.50). IGR was not associated with carotid plaque size.The PIR is associated with progressive carotid artery plaque size in women.

Verbal fluency (VF) impairments occur early in Alzheimer's disease (AD) and to a lesser extent also in normal aging. However, the neural underpinnings of these impairments are not fully understood. The present study evaluated whether VF impairments in early AD and normal aging rely upon common or different neuroanatomical correlates. We examined the association between VF performance and brain structure in 18 mild AD patients and 24 healthy elderly. Linear regressions were performed between accuracy and time intervals in VF scores and structural measurements of cerebral gray matter (GM) and white matter (WM) using MRI. Results showed that semantic VF correlated exclusively with GM in cerebellum, left temporal fusiform cortex, and WM in uncinate fasciculus, inferior fronto-occipital fasciculus and corpus callosum. Phonemic VF showed unique associations between intervals and WM in left-hemisphere tracts. The association between GM in hippocampus, subcortical structures and semantic accuracy differentiated patients from controls. Results showed that VF impairments are primarily associated with same structural brain changes in AD as in healthy elderly but at exaggerated levels. However, specific VF deficiencies and their underlying neural correlates exist and these clearly differentiate the initial stages of AD.

In a longitudinal population-based ultrasound survey, we evaluated the reproducibility of carotid plaque detection, off-line vs. online visual classification of plaque echogenicity and computer-assisted plaque echogenicity (grey-scale median, GSM) classification and plaque area measurements. The number of paired observations in the reproducibility analyses was 107 in the baseline study and 83 in the follow-up study. In addition, 198 and 222 images were selected from the baseline and the follow-up study for GSM- and plaque-area analyses. The total number of plaque images (11,160) was used to obtain comparative reference values. Despite good agreement in the reproducibility study (κ values ranging from 0.52 to 0.57), there was a substantial drift in online visual classification of plaque echogenicity during the survey period. Inter- and intraobserver agreement on computer-assisted GSM classification was substantial, with κ values (95% CI) of 0.77 (0.73 to 0.80) and 0.79 (0.75 to 0.84), respectively. A systematic bias in plaque area measurements was observed. Visual online classification may introduce systematic measurement errors that are not intercepted in a reproducibility study of restricted duration. Computer-assisted off-line classification had better reproducibility. However, the method is influenced by measurement errors, both in the outlining of the plaque and in the standardization procedure. (E-mail: einar.fosse@ism.uit.no )